WO2001054728A1

WO2001054728A1 - NOVEL REMEDIES WITH THE USE OF β3 AGONIST

Info

Publication number: WO2001054728A1
Application number: PCT/JP2001/000553
Authority: WO
Inventors: Kohei Ogawa; Hiroshi Umeno
Original assignee: Asahi Kasei Kabushiki Kaisha
Priority date: 2000-01-28
Filing date: 2001-01-26
Publication date: 2001-08-02
Also published as: CA2398199A1; AU2710301A; EP1258253A1; US20030018061A1

Abstract

Remedies containing at least one member selected from the group consisting of cholinolytics, monoamine reuptake inhibitors, lipase inhibitors, selective serotonin reuptake inhibitors, insulin, insulin secretion promoters, biguanide, a-glucosidase inhibitors, insulin resistance improving agents, HMC-CoA reductase inhibitors, anion exchange resins, clofibrate-base drugs and nicotinic acid-base drugs and a compound having a β3-agonistic activity. The β3 agonist has an activity of inhibiting urination disorder. When used together with a remedy for urination disorder such as propiverine, oxybutynin hydrochloride or tolterodine, it exerts an enhanced anti-urination disorder effect. When used together with an antiobestic agent such as sibutramine or orlistat, it exerts an enhanced antiobestic effect. When used together with an antidiabetic agent such as insulin, glibenclamide, acarbose or rosiglitazone, it exerts an enhanced antidiabetic effect. When used together with an antilipemic drug such as bezafibrate or pravastatin, it exerts an enhanced antilipemic effect.

Description

New cure and technical field using β 3 ^ S potion

The present invention relates to a novel therapy for β 3 agonist.

^ Adrenoceptors / 31, / 32, 33, are classified as ^ 1, stimulus of 1 increase in pulse rate, 32 stimulus induces old senile fibers, lower blood pressure, β 3 (i It is thought that it increases lipolysis of lunar fat cells and increases thermogenesis.Thus, ^ 3 agonists are useful for preventing diabetes, (Nature 309, P163-165 (1984), Int. J. Obes. Relat.Metab.Disord. 20, p 191-199 (1996), Drug Development Eesearch 32, p69-76 (1994) ), J. Clin. Invest. 101, p2387-2393 (1998)).

In ¾s, it was shown that the ^ 3 adrenergic receptor, in the detrusor muscle, ran 3 mm muscle strength. (J. Urinol. 161, p680-685 (1999), J. Pharmacol. Exp. Ther. 288, pl367-1373 (1999)). On the other hand, to date, the treatment of patients with leaks and urinary incontinence has been described as flavoxate, asoxybutynin, propiverine hydrochloride, and tolterodine. (Japanese Journal of Natural Sciences 113, pl57-166 (1999), Eur. J. Pharmaco. 349, p285-292 (1998)), however, there were side effects such as 渴, dysuria, and «5 (Clinical Urology 5¾ p277-285 (1998)), and the situation was not satisfactory.

In addition, as a side effect of sibutramine, which has been used as a tranny medicine, side effects such as increased blood pressure, blood pressure, and constipation have been reported (Int. J. Obesity, 21, S30-36 (1997)). Sibutramine is a monoamine reuptake inhibitor. Other drugs belonging to this group include milnacipran, duloxetine, and venlafaxine (Pharmaceutical Journal Vol. 36, No. 2, pl51-157 (2000)). Also, fluoxetine (Am. J. Clin. Nutr. 64, p267-273 (1996)), sertraline (J. Endocrinol. Invest. 19, p727-733 (1996)), paroxetine (Drugs 55, p85-120 (1998) )), And fluvoxamine (J. Clin. Psychiatiy 57, p346-348 (1996)) are considered to be useful as Tanabane Manga. Orlistat was also used as an anti-allergic drug; however, as a side effect, gastrointestinal disorders (fatty stool, increase, abdominal pain, urgency) have been reported as a side effect (J. Clin. Pharmacology 37, p453-473 (1997)).

Insulin, insulin secretion, biguanide, alpha darco Sidase inhibition U, insulin antagonistic improver. ^ Compounds having an insulinotropic activity (daribenclamide, glipizide, daliclazide, glimepiride, tolazamide, tolptamide, acetohaxamide, chlorpropamide, glicloviramide, meglitinidoca. Rehaglinide, nateglinide, etc. Mitiglinide in clinical trial (Japanese clinical special issue Diabetes 2, pl47-185

(1997), History of Medicine Diabetes 188, p491-495 (1999)). And, these insulin secretion J ィ i drugs: T stimulating greed, and with side effects, not always in a satisfactory state. There are metformin and pformin in biguanides, which are known to cause lactic acidosis (Medical History Diabetes, 188, p504-509h 999)). α-Darcosidase is used to prevent carbazole (Ann. Pharmacother. 30, pl255-1262 (19969), voglibose (Japanese clinical study 55 (Suppl.) pll4-119 (1997)). , P318-328 (1991)), Emiglitate (Eur. J. Clin. Ph. Acol. 41, p561-567 (1991)) Abdominal wisteria, increase in jars, loose stool, diarrhea (Advance in Medicine Diabetes, 188, 496-499 (1999)) Troglitazone, pioglitazone, thiazolidinedione derivative of rosiglitazone (Tokukaisho) Japanese Patent Application Laid-Open No. 55-222 636, Japanese Patent Application Laid-Open No. 60-51,189, Japanese Patent Application Laid-Open No. 6-157072, Japanese Patent No. 0306202 No. 8, Diabetes 37, pl549-1558 (1988), Diabetes 43, pl203-1210 (1994), Diabetes 41, p476-483 (1992), History of Medicine Diabetes, 188, p5 00-503

(1999)) Force ^^ Used on the floor. MC C-555 (Br. J. Pharmacol. 125, p767-770 (1998)), GI-262570 (WO97 / 31991) , JTT-501 (Diabetologia 42, pl51-159 (1999)), RP-297 (Diabetes 47, pl841-1847)

(1998)). Insulin 性改善改善改善体重体重体重体重体重, 体重体重 ί ί ί ί ί 性インスリンインスリン ί 体重インスリンインスリンインスリンインスリン体重体重体重インスリンインスリンインスリンインスリンインスリンインスリンインスリンインスリンインスリンインスリンインスリンインスリン改善インスリン.

HMG-c0 AMTmm mi Anion exchange resin, clofibrate drug, nicotinic acid drug for anti-lipid clots. HMG—Co A reductase inhibitor pravastatin (Pharmaceutical Journal 111, p469-487 (1991), US Patent No. 4,346,227), simpastatin (Atherosclerosis 101, pll7-125 (1993), USA Patent No. 4 4 4 7 8 4), Flupastatin (Clinical medicine 11 (Suppl. 1) pl53-180 (1995)), Atorvastatin (Am. J. Cardiol. 79, P1248-1252 997) ), Cerivastatin (Atherosclerosis, 135, pll9-130 (1997)), nispastatin (life Sci. 65, pl493-1502, 999)), S-4522 (Bioorg. Med. Chem. 5, p437-444 (1997)). Side effects of HMG-CoA reductase inhibitors include gastrointestinal disorders, elevation of thighs, elevation of PKC, and myopathy (Mol. Med. 31, P544-549 (1994)). There are cholestyramine (basic and clinical 16, pl50-169 (1982)) and colestimide (clinical medicine 12, _P 1263-1304 (1996)) as anion stimulant fat, and side effects include abdominal tenderness, constipation, and stiffness. Stool and hepatotoxicity can be increased. Colofibrate drugs include clofibrate, simfibrate, clinofibrate, bezafibrate, fenofibrate, ciprofibrate, and gemfibu oral gill. There is myopathy. Nicotinic acid drugs include nicotinic acid, nicomol, niceritol, and tocopherol nicotinate, and their side effects include hot sensation, flushing, low blood glucose, impaired glucose tolerance, gastrointestinal disorders, and high urinary paralysis (Mol. 31, p544-549 (1994)). In addition, the combination of clofibrate ^ fij and statin compounds ^! Is contraindicated due to dry toxicity. As mentioned above, these drugs {sister was not in a satisfactory situation.

There has been a long-felt need to provide new and useful superior medicaments that can be used in the treatment and prevention of dysuria, obesity, diabetes, hyperlipidemia, and the like. Disclosure of the invention

In order to solve the above-mentioned problems, the present inventors have confirmed that 3 agonists have an activity of suppressing pig damage. In addition, the effect of urinary dysfunction is stronger in combination with U-propiverine, oxiptinin hydrochloride, and tolterodine, stronger anti-micturition effect, more effective in combination with the tolvamines sibutramine and orlistat, and the anti-urinary effect. Stronger anticancer effect when combined with certain insulin, dalibenclamide, acarbose, and rosiglitazone, Stronger antihyperlipidemic effect when combined with antihyperlipidemic agents such as bezafibrate and pravastatin And found that the present invention was completed.

That is, the present invention {anticholinergic agent, monoamine #suppression inhibitor, lipase inhibitor, selective serotonin reabsorption inhibitor, insulin, insulin dispersant, biguanide, α-dalcosidase-insulin insulin-improving agent , HMG-octa reductase inhibitor, anionic resin, clofibrate drug, and nicotinic acid drug, and at least a compound having β3 pft activity. Or a therapeutic method that involves administering a combination thereof.

More specifically, the present invention relates to a (clothes comprising at least an anticholinergic agent and a compound having an activity of 313 f¾ca activity, a therapeutic drug for urinary incontinence, and administering the therapeutic drug. To be This is a treatment method for walking clothes and urinary incontinence.

Further, the present invention (including at least a compound selected from the group consisting of a monoamine reuptake inhibitor, a lipase inhibitor, and a 3¾¾ serotonin reuptake inhibitor, and a compound having β3 agonist activity). This is a method of treating obesity, and the administration of the cure is a TO.

The present invention further includes at least one selected from the group consisting of insulin, an insulin secretion inhibitor, a biguanide, an α-dalcosidase inhibitor, and an insulin bolus improver, and at least a compound having ^ 3 agonist activity. It is a drug for treating diabetes, and a method for treating diabetes that makes it difficult to administer the drug.

Further, the present invention has a 33 synergistic activity with any one selected from the group consisting of HMG-Co (a reduction inhibitor of ancillary acid, anionic thigh fat, clofibrate-based drug and nicotinic acid-based drug). A therapeutic agent for hyperlipidemia comprising at least a compound and a method for treating hyperlipidemia comprising administering the therapeutic agent. This specification incorporates the contents described in the specification of Japanese Patent Application No. 2000-733, which is the basis of the priority of the present application. BEST MODE FOR CARRYING OUT THE INVENTION

As the / 3 3p | power agent described in the present invention, for example, any of the following compounds represented by the following formula (I), general formula (II) or general formula (III), or a salt thereof It is preferred that

Formula (I);

Wherein, in the formula, an oxygen atom, a hydrogen atom, a logen atom or an (acid group, R ² represents a quaternary alkyl group or a benzyl group; R ³ represents 〇R, a halogen atom, a trifluoromethyl-grade alkyl group; NR ⁴ R ⁴ ', a nitro group or a cyano group, and R (O atom, lower alkyl R ⁴ and R ⁴ ′ represent a hydrogen atom, which may be the same or different from each other, a lower alkyl group, a lower alkyl group, a benzyl group or a SO group. shows the ₂ R ^5. R ⁵ represents a lower alkyl group or a benzyl group. W represents a hydrogen atom, diatomic (NH) or ¾¾¾ atom. * Means an asymmetric carbon atom.

"^ Formula (II);

[In the formula, R ^{6 represents an} O atom or a methyl group; R ⁷ represents an O atom, a halogen atom, a hydroxyl group, a benzyloxy group, an amino group or a hydroxymethyl group, and R ⁸ i represents an J atom, Represents a hydroxymethyl group, NHR ⁹ , SO ₂ NR ¹⁰ R ¹⁰ ′ or a nitro group, provided that R ⁹ represents an oxygen atom, a methyl group SO ₂ Rn, a formyl group or a CONHR ¹² ′, and R ¹¹ represents a lower alkyl group benzyl or NR ¹ oR ¹⁰ 'showing a. Moreover, R ¹⁰ and R ^10' good hydrogen atoms be different same or another, a lower alkyl group or a benzyl group. R ¹² Contact atom or I & Kyua R ¹² (shows an oxygen atom or a lower alkyl group; η is 1 or 2, W denotes a secondary crane atom, an oxygen atom or a sulfur atom. When η is 1, R ¹³ or in either one mosquito ¾ atom of R ^14, the other (When抹素atom, an amino group Asechiruamino a group and (FCK group. N 2, with R ¹⁴ (Contact J <atom, R ¹³ {i7j <atom, an amino group, Asechiruami cyano group or (Contact ] ^ represents a group. * 1 indicates an asymmetric carbon atom, * 2 and * 3 R ¹² and R ¹ ⁴ is a compound or its represented by that.] to asymmetric carbon atoms in the non-hydrogen atoms each坻

"^ Formula (III);

("I)

[In the formula, R ⁶ i represents an elemental atom or a methyl group; R ⁷ (an elemental atom, a halogen atom, a hydroxyl benzyloxy group represents an amino group or a hydroxymethyl group, and R ⁸ (fcK elemental atom, hydroxymethyl Grave NHR ⁹ , SO ₂ NR ¹⁰ R ¹⁰ 'or a nitro group, provided that R ⁹ (O atom, Methyl-SO ₂ R ", Hozoremyl group or CONHR ¹² ', R ¹¹ is a lower-alkyl benzyl group or NR ¹ oR ¹⁰ 'showing a. Moreover, R ¹⁰ and R ^10' good hydrogen atoms be different same or another, a. R ¹² atom or a lower § alkyl group showing an S及alkyl group or a benzyl group In addition, R ¹² (shows a J <primary atom or a lower alkyl group. W represents a secondary nitrogen atom, a free atom, a sulfur atom or a methylene group, and W represents the R of a secondary alkyl atom, a 瞧 atom or a sulfur atom. ¹⁷ (in your J atom, of R ¹⁵ or R ¹⁶ Deviation or the other is a hydrogen atom, the other hand ί Contact atom, an amino group, Asechiruamino a group also ifc group. Also, any age R ¹⁵ and R ¹⁶ of W force styrene groups are hydrogen atom, R ¹⁷ ( An oxygen atom, an amino group, an acetylamino group or a (fc acid group. * 1 represents an asymmetric carbon atom; * 2 an asymmetric carbon atom at the age of a ¹² -millimeter alkyl group.) Or a salt thereof represented by

The above-mentioned formula (1) of formula (I), and a freshly acceptable salt thereof, for example, a novel compound prepared by the method described below. Formula (II) and pharmaceutically acceptable salts thereof are described in, for example, WO99 / 01431. Further, the compound represented by the general formula (III) and a lexically acceptable salt thereof are described, for example, in JP-A-9-249623. In addition, in the present invention, it is sufficient that the / 33 agonist has ^ 3Fl activity, and includes, for example, the compounds described in US Patent No. 5,786,356 and WO98 / 43953.

In the HI formula), the halogen atom includes a fluorine atom, an atom, a bromine atom or an iodine atom: a possible force, of which a fluorine atom, an ass atom and a bromine atomic s' are preferred examples. The term “lower” of a lower alkyl group and a straight or branched »] carbon containing 1 to 4 carbon atoms mean methyl, ethyl, n-propyl, i-propyl. , N-butyl, i-butyl, s-butyl, t-butyl can be used. Further, it refers to a straight-chain or branched-chain acyl group containing a quaternary acryl group of && and a carbon atom having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, vivaloyl, Hexanoyl etc. are available.

Preferred hydrogen atoms, fluorine atoms, atoms, bromine atoms and Fennen groups, which are an oxygen atom, a hydrogen atom, a logen atom or an i-oxy acid group, are preferred.

R ² is a (&) alkyl group or a benzyl group. To be more specific, a methyl group Butyl group, benzyl n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group. Particularly preferred are methyl group and benzyl group.

In addition, R ³ハロゲン OR, a halogen atom, a trifluoromethyl group, a lower alkyl lower acyl group NR ⁴ R ⁴ ′, a nitro group or a cyano group (provided that R (an atomic atom, a lower alkyl group, a benzyl group or a fiber group) R ⁴ and R ⁴ ′ each represent a hydrogen atom, which may be the same or different from each other, and a quaternary alkyl group, a quasi-acyl group, a benzyl group or S 〇 ₂ R ⁵ R ⁵ represents a lower alkyl group or a benzyl group.), Of which OR is preferred and J is also preferred, and NR ⁴ R ⁴ 'is also preferred and J is preferred. R ⁴ and R ⁴ ′ are more preferably a hydrogen atom, a lower acryl group or SO ₂ R ⁵ , preferably an atom, a lower alkyl group or an optionally substituted lower acyl group. Listed as J.

W {Shows a variable atom, a dinitrogen atom and a nitrogen atom (NH) or a sulfur atom, of which dinitrogen nuclear is preferred. Any substituent may be used as long as it is a substituent of the lower acyl group and a substituent of the ί & higher acyl group in a reagent which is usually marketed, but is not particularly limited and is preferred. Examples of the substituent include an amino group, a hydroxyl group, an iS, and an afreoxy group which may be substituted with a lower alkyl group.

As the leaving group described below, it means an atom, bromine atom or iodine atom or a group which reacts to a sulfonic acid ester such as a mesyl group or a tosyl group.

In the above formula (I), * is an asymmetric carbon atom and can exist as two enantiomers of R and S. Not only optical isomers but also mixtures of two isomers in any ratio are included in the scope of the present invention. From the viewpoint of the pharmacological activity 好ましい, the preferred configuration and dimensional configuration R of the asymmetric carbon * in the ethanol amino chain are as follows.不 — [3— [2-[2-(7-Hydroxy-9 Η-carbazolyl 2-yloxy) ethylamino] —1-hydroxyethyl] phenyl] Asymmetric carbon of methanesulfonamide * Especially R-hydroxy form Is preferred as the W column.

In the compound of the present invention represented by (I), the combination of each of the antan groups is represented by [R fcK atom, halogen atom or (acid group. R ³ represents OR, halogen atom, trifluoromethyl group, Represents a quaternary alkyl group, a quaternary acyl group, NR ⁴ R ⁴ ′, a nitro group or a cyano group, and represents an atomic atom, a quaternary alkyl group, a benzyl group, or a substituted or unsubstituted acetyl group. , R ⁴ and R ⁴ ''m also be different from one in the same or each other tヽa hydrogen atom, a lower alkyl group, a lower Ashiru group, a benzyl group or a S 0 ₂ R ^{^5.} R ⁵ is a lower alkyl group Or a benzyl group You. ] Or a salt thereof is preferred.

Also, the combination of the respective fiber groups of the present invention "" ^ formula (I) is represented by [R ぉ J <elemental atom, halogen atom or {fcK acid group. R ³ represents OR, a halogen atom, a trifluoromethylalkyl group NR ⁴ R ⁴ ′, a nitro group or a cyano group. R (shows a J <primary atom, a lower alkyl group or a benzyl group, and R ⁴ and R ⁴ ′ each represent a hydrogen atom, which may be the same or different, a lower alkyl group or a benzyl group. Or a salt thereof, which is preferred.

~ «Compound of formula (I) For example, S ^ can be prepared by the following method.

(^ m "^ formula (IV)

[In the formula, R ^r represents an oxygen atom, a hydrogen atom, a hydrogen atom or a protected hydroxyl group, and * represents an asymmetric carbon atom.] A compound represented by the formula:

[In the formula, it represents a hydrogen atom, a 2, nitrogen atom (NH) or a sulfur atom. Y (J is a protecting group for an element atom or an amine, and R ³ ′ is OR,, a halogen atom, a trifluoromethyl class alkyl group, a class acetyl group NR ⁴ R ⁴ ′, a nitro group or a cyano group Further, R ′ represents a protecting group for a lower alkyl group, a benzyl group or a (Pennene group, even if it has a lower alkyl group substituent), and R ⁴ and R ⁴ ′ are the same or different. Different from each other, a hydrogen atom, a lower alkyl group, a lower benzyl group, a benzyl group or an amine protecting group or SO ₂ R ^5. R ⁵ represents a lower alkyl group or a benzyl group. And the resulting "^ formula (VI)

[Wherein, A represents an atomic atom, and R, R ³ ′, W, Y, and * each represent the same S¾ as above.] Wherein Y is a hydrogen atom And then further reduced to form "^ formula (VII)

[In the formula, Y represents a protecting group for amine, and A, R, R ³ ′, W and * have the same meanings as described above. The compound represented by the general formula (VIII)

XS0 ₂ R ² (VIII)

[Wherein, R ² represents a lower alkyl group or a benzyl group, and represents an X {i group].

The term “monthly 11” means a leaving group such as a sulfonic acid ester such as an atom, a bromine atom or an iodine atom, or a mesyl group or a tosyl group. HI (IX)

[Wherein, A, R ¹ ′, R \ R ³ ′, W, Y, and * each have the same meaning as described above. ], The age at which protecting groups are present in R ¹ ', R ³ ' and Y.

[R ¹ represents an oxygen atom, a halogen atom or an acid group, and R ³ represents an OR, a halogen atom, a trifluoromethyl grave alkyl, an acyl NR ⁴ R ⁴ \ nitro or a cyano group. A FUfc element atom, a lower alkyl group, a benzyl group or an optionally substituted higher acyl group, wherein R ⁴ and R ⁴ ′ are the same or different hydrogen atoms and different alkyl groups; group赚Ashiru group, a benzyl group or S_〇 _{^{^{2 R 5. R 2, R}}} 5, W and * their respective as defined above.] in are compounds force ^ represented.

When R ¹ ′ and R ³ ′ contain a hydroxyl-protecting group, there are no particular restrictions on the group of the acid group, provided that they are commonly used, but such protecting groups can be easily and easily deprotected. Examples include trialkylsilinole groups, alkoxyalkylacyl groups, and the like. Introduced and demyelinated the introduction and demyelination of these hydroxyl protecting groups (eg, Protective Groups in Organic Synthesis, Wiley-Interscience Publication, TW Greene, PGMWuts et al.) (The known method described in this gc can be used. For example, in the introduction of a t-butyldimethylsilyl (TBDMS) group, in the presence of an acid scavenger, t-butyldimethylchlorosilane or t-butyldimethylsilyl is added to the alcohol. An example is shown in which a silylating agent such as trifrenoleolomethanesulfonate is allowed to act.Amount of the silylating agent is usually 1 to 1.5 times the molar amount of alcohol. It is usually performed in an inactive body. Inerts include dichloromethane, tetrahydrofuran, acetonitrile, pyridine, etc. Gerare N, N- dimethylformamide can be exemplified as preferred W column. Per alcohol lg use amount of the inert medium, as. An acid scavenger to be. 1 to 5 ml 禾雖 mosquito 顿示 Toryechiruami , N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine and the like, and imidazole is preferred as ^ J. The amount of the acid supplement is usually 1 to 3 times the amount of alcohol. In this reaction (usually, the reaction is preferably carried out at 120 to 80 ° C., particularly at 0 ° C. to room temperature, preferably for 1 to 5 hours.

Introduction of benzyloxymethyl (B OM) group {The reaction is carried out by reacting chloromethylbenzyl ether with alcohol in the presence of an acid scavenger. Addition amount of chloromethylbenzyl ether Mono-Mg is usually 1 to 1.5 times that of alcohol. This reaction is preferably carried out in an inert atmosphere. Preferred examples of the inert resin include tetrahydrofuran, thiocetonitrile, N, N-dimethylformamide, and the like. The amount of inert inert used is about 1 to 5 m 1 per g of alcohol. Preferred examples of the acid scavenger include N, N-diisopropylpropylethylamine, such as triethylamine, pyridine, N, N-dimethylaminopyridine and the like. The addition amount of this acid supplement is usually 1 to 3 times that of alcohol! / FiJt. This reaction is preferably carried out at a temperature of from 120 to 80 ° C, particularly from 0 ° C to room temperature gjg, for example, preferably from 1 to 5 hours.

In addition, the reaction is carried out by reacting an alcohol with an acetylating agent such as glacial acetic acid or acetyl chloride in the presence of an acid-capturing agent for introducing an acetyl (Ac) group. Amount of acetylating agent Normally 1 to 3 times moles of alcohol! You will be shown. This reaction is preferably carried out in an inert atmosphere of ^ Φ: preferably. Examples of inactive '1' are (preferably tetrahydrofuran, acetonitrile, dichloromethane, pyridine, etc. ^!) Inactive amount is shown as 1 to 5 m1 MJg per 1 g of alcohol. Examples of acid scavengers include triethylamine, N, N-diisopropylethylamine, pyridine, and N, N-dimethylaminopyridine. This reaction (usually at 20 to 80 ° C, especially at 0 ° C to room temperature MJ ^ is preferable, for example 1 to 5 hours It is important to react.

In addition, when Y, R ⁴ or R ⁴ ′ contains a functional group of an amino group, examples thereof include an aliphatic group such as an acyl group, an acyloxy group, or an aralkyl group which can be easily deprotected. A benzyl group, a benzyl group, a naphthylmethyl naphthylmethyl group, and the like are particularly preferred as aralkyl groups that can be easily removed, and particularly preferably a benzyl group. Examples of the aralkyl group include, for example, an aralkyl group containing 7 to 16 carbon atoms. Benzyl tomb, phenyl 3-phenylpropyl 4-phenylbutyl, etc., and (1-naphthyl) methyl 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, etc. On the naphthyl group, an appropriate group such as an alkyl group, an alkoxy group, and a halogen atom may be provided at an appropriate position. The introduction of these protecting groups may be performed by a known method described in the above-mentioned Fuji.

"^ The compound of formula (VI) (a sickle substance and a chemical compound represented by HI (I) ^) is an important intermediate in the synthesis of ί (#». "" ^ The compound of formula (VI) IV) and ^: a compound represented by the formula (V) can be converted to a normal ^ :, for example, dimethylsulfoxide, kanji, or {^: ether, dimethylformamide, dimethylacetamide or 2 —Alco such as butanol

-It is obtained by reacting in a toluene-based organic solvent. π 示 δ In many cases, the compound represented by the formula (IV) and the compound represented by the general formula (V) are used in equimolar amounts, but it is preferable to use | J amount of the conjugated compound represented by the formula (V). That power is. Although the reaction time is measured, it is usually indicated by the flow of Nada, which is intercepted from room temperature. The reaction time can be appropriately reduced depending on the reaction conditions and the like. Usually, the reaction time should be terminated when the rope ratio becomes the maximum. In the reaction, trimethylsilyl acetoamide (TMSA), N, O-bis ( It has been reported that the addition of trimethylsilyl) acetoamide, hexamethyldisilazane (HMDS), and bis (trimethylsilinole) urea can improve the reaction time and yield (Tetrahedron Lett., 1998). 6 years, 27 volumes, 2 451 pages), which can be used to measure this method.

The compound of the formula (VII) is also a novel substance and is an important intermediate for the synthesis of the compound of the formula (I), and reduces the nitro group of the formula (VI) to give an amine (aniline). It can be obtained by In the reduction, if the substituent in (VI) is a calcium atom, it is converted into a protecting group for amine in advance, and the reduction reaction is performed, for example, in a solvent such as methanol, and hydrogenated in the presence of a catalyst for Pt. Or (in the presence of i »or divalent tin, in a system using transmutation, etc.

The compounds of formula (IX) is also a novel substance, "^ formula is an if ^ manner as an important intermediate for compound synthesis represented by (I), formed with various substituents on R ^2, ~« formula The compound represented by (VIII) has been described in the literature (C. kaiser et al., Journal of Medicinal Sole Chemistry-(J. Med. Chem.), 1974, Vol. 17, p. 49). of by carrying out the method Suruhoni spoon of Amin of the compound of general formula (VII) (Anirin) with is formula (IX) compound Ru indicated by force. in addition, R, a hydroxyl group in R ³ 'and Y Alternatively, of the amine groups, the existing dehydrating groups are desorbed according to the desorption method observed, and are represented by the formula (I). Rei dani ^! Can be helped.

The sulfonation described above can be performed, for example, by reacting a compound of the formula (VIII) with a compound of the HIS formula (VII), which is commercially available, from ice-cooled to room temperature in a sea of pyridine or the like. And when the deprotection may be performed together be sequentially, but preferably of Amino groups in R ¹ 'or R ^3' ^ ¾ Hiroshi Y of 7j <m group in, R ³ '髓基It can be done in order. As a condition for deprotection, use a catalyst such as a benzyl group of the hydroxyl group of R ¹ ′ and R ³ ′ such as noradium or nickel to decompose hydrogen in methanol or the like. Alternatively, deprotection is performed by using a Lewis acid such as boron tribromide in methylene chloride such as a benzyl group or a methyl group as a protecting group for the hydroxyl group of R ¹ ′ and R ³ ′. The deacetylation of the acetyl-protected hydroxyl group at R ¹ ′ and R ³ ′ is carried out using known ester hydrolysis conditions. As a specific example, a method of heating from room temperature to gentle reflux using alkali in alcohol can be used. Addition of acetic acid in tetrahydrofuran and 3 to 5 moles of tetrabutylammonium fluoride in tetrahydrofuran, such as a triethylsilyl group for protecting the hydroxyl group of R ¹ ′ and R ³ ′, and treatment at room temperature for 30 minutes to 5 hours Can be removed by Benzyl protecting group for the amino group in Y and R ³ '{Hydrogen decomposition in methanol or the like using a catalyst such as radium or nickel to deprotect. In addition, deprotection is achieved by heating at room temperature in a solvent such as methanol or the like, which is the acetyl group of the ί ^ group of the amine in Y or R ³ 'at room temperature. it can.

The compound represented by the formula (IV) {is known, and the racemic form is obtained by acidifying a known corresponding styrene with an oxidizing agent such as m-chloroperbenzoic acid at 0 ° C. to room temperature in dichloromethane or methane. It is obtained by doing

Also, as an alternative, "^ -expression (X)

[Wherein, R ¹ 'has the same meaning as the previous expression, and represents a B 〖i ^ atom, a chien atom, or an iodine atom. ] Is reduced with Shimoyuki's cranes, and the compound of formula (XI)

[Wherein, R and * each represent the same 辦 as above, and A (shows a J atom, B (i ^ ¾ atom, a bromine atom or an iodine atom.), And a substituent B is added as necessary. It can also be obtained by replacing iodine with a chlorine or bromine atom with iodine, followed by epoxidation with an alkali treatment, that is, reduction of the compound represented by the formula (X) represented by the general formula (XI) The steric * of the hydroxyl group of the compound can be obtained by using a reducing agent such as racemic age borane.

Regarding * in the formula (XI), it was attempted to obtain an optical isomer of R or S (XII)

(XII)

And the like. (B in the formula (indicating a boron atom) may be used. That is, the compound represented by the general formula (X) may be used in the presence of the above-mentioned chiral auxiliary. The above reduction reaction is preferably carried out in a solvent such as tetrahydrofuran.The preparation of these chiral auxiliaries and the reaction thereof are described in the literature (EJ Corey et al., Journal The method may be performed according to J. Org. Chem., 1991, Vol. 56, p.

A compound obtained by reducing the compound represented by (X) to form the formula Cxi), and then substituting the iodine atom or bromine atom for iodine atom, and, if necessary, ± Further, a method is shown in which a iodinating agent such as sodium iodide is used in an amount of 3 to 10 times the amount of the bromide in a solvent such as acetone, and caloheating is carried out for l to 3 hours under reflux ^ a. Thereafter, the compound of the formula (IV) can be obtained by epoxidation in a solvent such as methanol at 0 ° C. to room temperature in the presence of 1-2 equivalents of an aqueous solution of sodium hydroxide or the like. When the H¾ formula (IV) is obtained from the HI formula (XI), the stereochemistry of the asymmetric carbon * is retained. That is, R body from R body, S body from S body I can get strength.

"^ The compound represented by the formula (X) (a known and commercially available product, such as (Α A. Larsen et al., Journal of Medicinal Chemistry ( Med. Chem.), 1967, Volume 10, p. 62 or C. kaiser et al., Journal of Medicinal Chemistry! Med. Chem.), 1974, 1 (Vol. 7, p. 49).

On the other hand, a compound of-(V) (a standard substance, which is an important intermediate in the synthesis of the compound represented by the formula (I)).

Compound of formula (V) Hi (XIII)

[Wherein, Υ represents a protecting group for the amine, and a compound represented by an X ′ «^ atom, a bromine atom or (acid group).

[In the formula, a Wi fiber element atom, a 2, -element element (NH) or a sulfur atom is shown. R ³ ′ represents OR ′, a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower acyl grave NR ⁴ R ⁴ ′, a nitro group or a cyano group. R ′ is a quaternary alkyl group or an optionally substituted {quaternary sacyl group, a benzyl group or a phosphoric acid group, and R ⁴ and R ⁴ ′ are the same or different from each other. A hydrogen atom, an iS and an alkyl group, a quaternary acyl group, a benzyl group, an amine protecting group or SO ₂ R ⁵ . R ⁵ represents a lower alkyl group or a benzyl group. :] Can be obtained by reacting a compound represented by the following formula: Y, R ⁴ or R ⁴ ′ is an amine deviating group and is not particularly limited as long as it is commonly used as an amine protecting group.Examples include (a benzyl group, benzyl group, which can be easily deprotected, and benzyl group). Examples include a xycarbonyl group, a substituted benzyloxycarbonyl group, a t-butoxycarbonyl group, an acetyl group, and a trifluoroacetyl group.

"^ Reaction of formula (XIII) with general formula (XIV) During the rinsing, it is necessary to carry out from room temperature to the flow of Nada, which has been restored. Solvents include dimethylformamide, dimethylacetamide, acetonitrile, diglyme, tetrahydrofuran carbonate, and bases such as potassium carbonate, sodium carbonate, sodium hydroxide, 7_potassium oxide, triethylamine, pyridine, 7_sodium sodium, It is preferable to use sodium methoxide or the like in an amount of 1 to 10 times the molar amount of the formula (XIV).

When the reaction is slow, use the method described in the literature (Bull. Chem. Soc. Jpn., 1982, Vol. 55, pp. 250), or use an improved method thereof. ^: Formula (V) [Y fiber amine protecting group. ] Can be synthesized. For example, in dimethylformamide or acetonitrile, the compound of formula (II) is 2 to 5 times the mole of the compound of formula (XIV), and the mole of 40% potassium fluoride-alumina is 5 to 10 times the mole of the compound of the formula (XIV). As the ¾m method (add potassium iodide 0.1 to 0.5) and react at room temperature to 90 ° C.

Further, by deprotecting the individual group Y of the amine, the amine compound of the formula (V) [Υ (meaning an O atom) is obtained. In a solvent such as, for example, hydrogen can be deprotected by decomposing hydrogen with respect to noradium monocarbon, or odor can be deprotected by waking up with monoacetic acid. The compound represented by the formula (V) [Y (where an oxygen atom is asterisk)] can be obtained by washing with an alkali in a solvent such as methanol.

Further, the compound can be synthesized by supplying a compound of the formula (XIII), wherein X, is a 7-end group, and performing a Mitsunobu reaction with the compound of the formula (XIV). That is, the reaction force | J in the presence of 1 to 10 equivalents of triphenylphosphine and 1 to 10 equivalents of getyl azodicarboxylate in tetrahydrofuran or the like at 0 C to room temperature.

Compound of general formula (XIII) A commercially available amino alcohol is first protected with an protecting group Y to protect the amine, thereby obtaining an X'-hydroxy compound; Then, the corresponding bromide or iodine can be synthesized by subjecting the hydroxyl group to rebromination or iodination by a conventional method. Also, it is easily obtained by brominating a benzyl group, a commercially available benzylaminoethanol, and is preferable. Further, if the aminobromide can be easily taken in, it can be obtained by protecting the amine with the protecting group Y. As an example, the power of reacting commercially available 2-bromoethylamine bromate with benzyloxycarbonyl chloride in methylene chloride in the presence of triethylamine is shown.

The compound of the general formula (V) can also be obtained by the following method. That is, ~ ^ expression (XIV) and HIS expression (XV) X "(xv)

[In the formula, X represents a thigh group, and X ′ ′ (means a logen atom. A leaving group represents a group such as a sulfonic acid ester such as a fossil atom, a bromine atom or an iodine atom, or a mesyl tosyl group. With the general formula (XVI)

[Wherein, W, Z and R ³ ′ each represent the same as described above. ], And Z is represented by the general formula (XVII)

YNH ₂ (XVII)

[In the formula, a protecting group for a Yifc element atom or an amine is shown. And the compound of the formula (V)

Among the compounds of ~ «formula (XIV), W is a secondary atom, a long ³ 'mosquito ¾ ^ group, black hole or compound novel compound other than methyl group, it can be synthesized by the following method. That is, a compound of the R ³ 'group was described in the literature (SP Popri et al., Indian J. Chem. Sect. B, 19776, 14B Vol., P. 371). By reacting this with an alkyl halide in the presence of a salt such as potassium carbonate, a compound in which R ³ ′ is OR ′ can be synthesized. Further, a protecting group can be introduced by the above-described method for introducing a protecting group. Further, a compound in which R ³ ′ is a bromine atom or a cyano group is described in the literature (RR Tidwell), et al., Journal of Medicinal Chemistry, Eur. J. Med. Chem. The compound described in Vol. 32, p. 781) can be synthesized by deprotection according to ordinary methyl ether deprotection conditions. Also,

Compounds with ^^ atoms are described in the literature (SP Popri et al., J. Med. Chem., 1976, 16: 425). Can be synthesized by removing the same as above. In addition, compounds of the R ³ 'alkyl group are described in the literature (R. S. Kapil) et al., Compounds synthesized according to the method described in Indian Journal of Chemistry, Section B (Indian J. Chem. Sect. B), 1988, ∑3B, pp. 296). Can be synthesized by deprotection in the same manner as described above. Furthermore, as the 另! Method, ~ «formula (XVIII)

(XIX)

[Wherein, R ⁶ (indicates a substituent group of the pigeon group; indicates a B boron atom in the equation.)]

(XIX)

[Wherein, X is the thigh root, and R ³ ′ has the same meaning as described above.] The compound represented by the general formula (XX)

[Wherein, R ⁶ and R ³ ′ each have the same meaning as described above. The compound of formula (XXI) can be obtained by subjecting the compound represented by! To a further reductive ring closure.

[Wherein, R ⁶ and R ³ ′ each represent the same fiber as above. Subsequently, by deprotecting R ⁶ , the compound represented by the formula (XIV) is obtained. -Compounds of (XVIII) and HIS formula (XIX) Obtained by obtaining a commercial product or adding a protecting group to the commercial product. Suzuki Reaction Magazine (Norio Takaura, Suzu ^^, Journal of Synthetic Organic Chemistry, Vol. 46, pp. 848 (1988); Yuki Gosei Kagaku Kyoukaishi, vol. 46, 848 (1988)) One method is to perform 5S according to the method described in the literature (CW Holzapfel et al, Heterocycles, vol. 48, No. 8, 1513-18 (1998)).

Compound of the general formula (XXI) The compound can be synthesized by applying the method described in the literature (JIG Cadogan et al, J. Chem. Soc., 1965, 4831). That is, the compound of the formula (XX) is heated in the presence of trialkyl phosphite or triphenyl phosphite to cause a reductive ring-closure reaction to obtain a phyllazole derivative of the general formula (XXI). Triethyl phosphite is preferred as the phosphite used, and the amount used is, for example, 2 to 10 equivalents, and more preferably 2 to 4 equivalents. The reaction is indicated at 80 ° C to 180 ° C, more preferably at 130 ° C to 170 ° C. The reaction time is indicated from 1 hour to 24 hours, preferably from 3 to 10 hours. Thereafter, the compound represented by the formula (XTV) is obtained by deprotection of R ⁶ in a conventional manner.

In addition, in ~ «Eq. (XIV), W is the subject atom's literature ((. 0. Stransky) et al., Journal of Chemical Society, Perkin Transaction 1 (J. Chem. Soc. Perkin Trans. I ), 1982, p. 1605), by deprotecting the methyl group of 3,7-dimethoxydibenzofuran according to a conventional method, and then alkylating or protecting only one of them. Can be Also, the W force% / yellow atom is described in the literature (MM Joullie et al., Journal of Medicinal Chemistry, 1978, pp. 21 and 1084). The reduction of 3,7-dihydroxydibenzothiophene 5,5-dioxide described in 4) with lithium aluminum hydride to 3,7-dihydroxydibenzothiophene, followed by alkylation or protection in the same manner as above, Compound power

Also, as an alternative, HI formula (XI)

[In the formula, A represents a protecting group for the acid group, and B represents a leaving group as described above. Also, R ¹ 'and * Has the same meaning as described above. And the HI formula (V)

[Wherein, Y represents a nitrogen atom or an amine-protecting group, and W and R ³ ′ each have the same meaning as described above. HI (VI) [wherein, Α (indicates the base group, R ¹ ′, R ³ ′, W, Y and * have the same meanings as above.) The compound power of the formula (I) is obtained in the same manner as described above.

Introduction and removal of equipment can be performed according to the above-mentioned method.

Also, as an alternative, formula (X)

[Wherein, R "has the same meaning as described above. B represents a leaving group in the same manner as described above.] And a compound represented by the formula (V): wherein W, Y and R ³ ′ Has the same meaning as described above.] Is reacted with-(XXII)

[Wherein, R ^r , W, Y, and R ³ ′ each have the same meaning as described above. The compound represented by the formula (VI) [A (indicating an atomic atom)] is obtained by reducing the carbonyl group by the same method as described above. In a similar manner to ~ «the compound of formula (I) can get.

-«: Reaction of the compound of formula (X) with the compound of formula (V). Literature (A. A_ Larsen et al., Journal of Medicinal Chemistry (J. Med. Chem .;), 1967 Year, Vol. 10, p. 462), and ice-cooled in polar solvents such as acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide in the presence and absence of amine as an acid trough. The reaction is carried out at 60 ° C from below, and the carbonyl group is reduced with a reducing agent such as sodium borohydride or sodium hydrogen sodium borohydride at room temperature under ice-cooling at room temperature. Deprotected and {5}. In order to obtain the optically active substance, optical resolution is carried out by the method described later, or at the time of reduction, the thigh described above, or various literatures (for example, (K Achiwa) et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 1995, Volume 43, pp. 748 or (R Noyori et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), 1 Asymmetric reduction with a 7j element-supplying compound may be performed in the presence of a known asymmetric catalyst described in, for example, 1996, Vol. 118, p. 2521).

As a further alternative, the HIS formula (XXIII)

(XXIII)

[Wherein, R ¹ ′ has the same meaning as described above. And a compound represented by the general formula (V): embedded image wherein W and R ³ ′ each have the same meaning as described above. And the carbonyl group is further reduced by reacting the compound represented by the formula (VI) [wherein A and Y {represent an atomic atom, R ¹ R ³ 'and W has the same meaning as described above. ] And, if necessary, protecting A and Y in a conventional manner, and then reducing the nitro group in the same manner as described above to obtain a compound of the formula (VII). Can be helped. Hereinafter, the compound of the formula (I) is obtained in the same manner as described above.

This reaction is usually carried out in a medium, and is carried out in the presence of a suitable reducing agent capable of first reducing the Schiff base obtained by the condensation reaction and simultaneously reducing the carbonyl group to the hydroxy group. Examples of the reducing agent include sodium sodium boron, sodium hydrogen cyanide boron, and lithium lithium sodium cyanide 7_. The amount of phenyldalioxal is 1 to It is used in an amount of 3 moles, preferably 1 to 1.5 moles. The reaction is carried out by a suitable method, but usually the reflux temperature of the solvent measured from room temperature is indicated. The reaction time can be selected depending on the reaction conditions and the like. Usually, the reaction may be terminated at the point where the extinction rate is maximized. As an example, the reaction may be carried out in an alcoholic solvent such as methanol or ethanol, preferably at a low temperature. It is carried out in the presence of sodium borohydride In order to obtain an optically active substance, optical division may be carried out by the method described later.

~ ¾ By easily oxidizing the acetophenones substituted with the compound R ¹ ′ of the formula (xxrii) with an oxidizing agent such as selenium dioxide in water or an organic solvent such as ether such as dioxane tetrahydrofuran. Can be obtained. As another method, the method described in the literature (Journal of the American Chemical Society (J. Am. Chem. Soc.), 1995, Vol. 79, Vol. 79, page 6562) is used. Can fiber.

Alternatively, the HI formula (XXIV)

[Wherein, A represents a protecting group for an acid group, R ¹ ′ and * represent the same kneading as described above], and a compound represented by the formula (XVI)

[Wherein W, R ³ ′ and Z each represent the same fiber as above. In the reaction with a compound represented by the formula (VI) [wherein, Y represents an oxygen atom, A represents a protecting group of a pennant group, and R ^r , R ³ ′ and ¹ W represent the same as above. The compound of the formula (I) can be synthesized in the same manner as described above after obtaining the compound of formula (I).

The coupling reaction with an amine is carried out in an organic solvent, if necessary, in the presence of a proton acceptor such as a tertiary amine (for example, triethylamine). The reaction is carried out according to the general formula (VI) [where Y ( atom Is shown. ] The compound power of The term “V” having 11 atoms and {atom, bromine atom, or iodine atom means a group involved in the above reaction such as a sulfonic acid ester such as a mesyl-tosyl group. An example of the reaction conditions and the like is that the amount of the amine of the formula (XXIV) is 1 to 10 times the molar amount of the compound of the formula (XVI).

This reaction is preferably performed in an autoclave, and the solvent used is alcohol such as methanol, ethanol, or butanol, methylene chloride, halogenated bj such as chloroform, or the like. Examples thereof include tetrahydrofuran and dioxane. The reaction is generally between 10 and 150 ° C, preferably between 70 and 130 ° C. The reaction time is generally 5 to 100 hours.

The compound of the formula HIS (XXIV) can be obtained by hydrogenation of the fiber mandelonitrile fibered with R ¹ ′, for example, by reacting in the presence of a catalyst such as Raney nickel. Substituted mandelonitrile is a substituted benzaldehyde and cyanide, and is obtained as a racemate from the reaction of sodium cyanide and sodium sulfite and scaled according to routine methods and techniques. The formation of 14 optically active salts and diastereomers can easily separate them into optically active isomers. In addition, an optically active compound of the formula (XXIV) is reacted with ammonia in the presence of a commonly used condensing agent to react an optically active carboxylic acid obtained by decomposing optically active mandelonitrile with carohydrolysis. It can be obtained by continuous reduction. The various compounds described in the present application may be purified as necessary. For example, using various known chromatographic methods (column, flash column, thin layer, high-speed liquid), for example, the Rf value of the specification It can be used as an indicator.

As mentioned above, compounds of formula (I) may exist as two different optical isomers. In addition, there can be up to eight compounds of the formula (II) and up to four optical isomers of the formula (III). Both the process isomers and the racemic mixtures of the present invention can be provided. It does not alter the stereochemistry involved.

Thus, starting from compounds of the general formula (X) or (XXI II) which have no asymmetric carbon, or starting from compounds of the general formulas (IV), (XI) or (XXIV) as racemates And, he is sung in the race. Similarly, starting from the l-isomer of the compound of formula (IV), (XI) or (XXIV), for example, the R isomer of formula (IV), only the R isomer is activated and the formula (IV),

If the optically active isomer of the compound (XI) or (XXIV) is used, a pure isomer can be obtained.

A mixture of the two enantiomers (racemic) when forced to undergo camphorsulfonic acid, An acid or an addition salt with an optically active acid such as substituted mandelic acid can be separated by an appropriate method such as fractional crystallization. Fractional crystallization can be carried out using a suitable solvent, preferably ifi and an alkanol (eg, ethanol, isopropynole alcohol and mixtures thereof).

Each set of 14 enantiomers can be separated into fog isomers by formation of diastereomeric salts, chromatographic or other means using optically active columns. If one of the starting materials is optically active The mixture of diastereomers obtained in this manner is separated into the isomers by the above-described method, and is separated into optically active isomers, so that only the more active isomer is used. It is possible to improve the effect or dissociate side effects, and is preferable as a medicine.

It is desirable to add these compounds and a carrier that is useful as a medicine and that is tolerated as necessary, to form a medical device. As a lexically acceptable carrier, binders such as mm. Carboxymethinoperulose, mi lubricants, additives and the like are indicated. When these compounds are administered to humans, they can be orally administered in the form of tablets, powders, powders, capsules, sugar fibers, tablets, syrups, and the like. In addition, parenteral administration such as a thigh preparation is also possible. The dosage varies depending on the patient's age, weight, and the degree of symptoms, but is administered within a day or twice a day. It is generally administered daily for a period of several months to several months, but the daily dosage and administration period can be increased or decreased depending on the patient's symptoms. It may be mixed in one container upon administration, but may be stored in another container in some cases and administered substantially simultaneously to the same patient upon administration.

Urine ^^ In general, it is delicate that "involuntary urine leaks that can be objectively proved and cause problems in daily life" can cause problems. "I feel unpleasant and can not stand it." (New Current 10 (18) p2-7 (1999)). Obesity Normally, the BMI (Body Mass Index) refers to people with a body mass index of 25 or more. In this condition, it is said that the proportion of people who develop hypertension, hyperlipidemia, and diabetes is higher than those who have a blood mass of 25 or less ( Nature 404, p635-643 (2000)). Diabetes Mellitus is classified into type II diabetes and type II diabetes. In the present invention, type II diabetes is a more preferable treatment. Type II diabetes Insulin fiber is observed. Judgment course for diabetes Diabetes fasting β 140 mg dl or more, 75 g sugar loading It is known that 2 hours later fiber is 200 mg / dl or more (Japanese Clinical Diabetes 1, 55 ρ247-253 (1997)) . It is a risk factor for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, especially hypercholesterolemia and atherosclerosis. Diagnosis of hyperlipidemia (Serum cholesterol 220mg / dl or more, tridalicelide There is a description that it is 150 mg / dl or more and HDL (high iS lipoprotein) monocholesterol is 40 mg / dl or less (Molecular Medicine. Vol. 31, p544-550).

In the present invention, の of the anticholinergic agent muscarinic receptor is as described in Vol. 52, No. 5, p. 277-287 (1998), and specifically, for example, 麵 flavoxet, transmutated oxyptinin, propiverine, Tolterodine cadaver (Japanese Journal of Kikuri Studies 113, pl57-166 (1999), Eur. J. Pharmaco. 349, p285-292 (1998)), especially preferred are asoxyxybutynin, propelled propiverine and tolterodine. Is exemplified.

The monoamine reabsorption inhibitor Inhibits reuptake of serotonin and noradrenaline and increases both monoamines is described in Pharmaceutical Journal Vol. 36 No. 2, pl51-157 (2000) .Specifically, for example, sibutramine, milnacipran , Duloxetine, Benrafaxinka, but especially preferred as Sibutramine mosquito.

Monotonous Serotonin Reabsorption Inhibitor (SSRI) Monodrug and Pharmaceutical Journal Vol. 36, No. 2 P137-140 (2000) It has only the ability to inhibit serotonin reuptake and has no ability to reuptake norradrenaline-dipamine. ), And specifically include, for example, fluoxetine, sertraline, paroxetine, and fusoleboxamine.

In addition, it is described in J. Clin. Pharmacology 37, p453-473 (1997) that a lipase inhibitor is a lipase inhibitor of gastric stomach and inhibits the degradation of triglyceride in food. Orlistatka ^ Preferred.

Insulin secretion ^ I agent Knee 3 cells K _A1 channel bundles IJ Intensification of insulin secretion from / 3 cells by intensifying IJ As described in Diabetes 188, p309-313 (1999). Typical examples include dalibenclamide, glipizide, daliclazide, glimepiride, tolazamide, tolptamide, acethexhexamide, chlorpropamide, glicloviramide, meglitinide, levaglinide, nateglinide, mitiglinide, and especially preferred repaglinide, mitiglinide, mitiglinide, and mitiglinide. Italy J is shown.

Biguanide Methophonolemin, Pforminka Peger.

α-Dalcosidase inhibitor Inhibition of α-dalcosidase in the small intestine to prevent sugar from being absorbed from the ciliated epidermis The history of force medicine Diabetes 188, 496-499 (1999) (For example, (acarbose, voglibose, miglitol, emiglitor, toka), especially acarbose and voglibose are preferred.

Insulin ¾M-improving agent An agent that improves insulin maleness, which is one of the causes of type II diabetes, and which corresponds to PPARy Pl strength medicine at a certain time (diabetes 188, p500-503 (1999)). Ingredient Physically, for example, troglitazone, pioglitazone, rosiglitazone, MC C-555, GI-266,570, JTT-501, KRP-297 power!], Especially pioglitazone, rosiglitazone , MC C-555, GI-262,570, JTT-501, KRP-297.

HMG-CoA reductase inhibitor {Cholesterol synthesis ¾ An inhibitor of HMG—C0A reductase, which is an element of S, resulting in a decrease in blood cholesterol (Mol. Med. 31 , P544-549 (1994)). Specific examples include pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, nispastatin, and S-4522. Anion exchange dish fat (base anion exchange fat, which binds to bile acids with feces and is contained in feces, is described in 16, 16, 50-169 (1982). Cholestyramine, cholestimido ^ ij are indicated.

Clofibrate, which has PPARa agonizing activity, and is responsible for converting fat (Mol. Med. 37, p83-90 (2000)). Specific examples include black fibrate, syn fibrate, crino fibrate, bezafibrate, fenofibrate, ciprofibrate, and gemfibrose.

Nicotinic acid drugs Nicotinic acid, Nicomol, Niceritol, Tocopherol nicotinic acid.

Summary of the Invention Toxicologically, therefore, higher doses can be administered. Using the ratio between various toxicities and the efficacy (eg, effective amount such as / 33 activity) in each application as an index, ^ 3 agonistic drug use, use of each drug and insect, and combination use of β3 agonist and each drug When the indices in use are compared, the indices at the time of treatment by the combination according to the present invention are high, and their safety and effectiveness are easily enhanced.

As an index of toxicity, it can be measured, for example, as a side effect of anticholinergic agents. It can be measured by examining the suppression of pilocarpine-induced salivary secretion in accordance with the method of this book (113, ρ156-166 (1999)). Elevated blood pressure, which is a side effect of sibutramine, can also be used as an indicator of toxicity. This blood pressure rise can be measured using a pressure transducer. Gastrointestinal disorders (fatty stool, increase in stomach ache, abdominal pain, urgency), which are listed as side effects of orlistat, can also be used as indicators of toxicity. This gastrointestinal disorder can be examined by clarifying the disgust. Enhancing appetite, which is a side effect of insulin secretory drugs, can also be an indicator of toxicity. This animal can be used to monitor body weight fluctuations, and it is another toxic substance It can be determined by examining the blood glucose concentration. Loose stools and diarrhea, which are side effects of Ct dalcosidase inhibitors, can also be used as indicators of toxicity. It is also possible to examine the stool administered to the loose stool and diarrhea animal by examining the stool and removing the dead matter. Weight gain, which is a side effect of insulin sensitizers, can also be used as an indicator of toxicity. This weight gain can be determined by administering to animals and weighing them. Gastrointestinal disorders, which are side effects of HMG-CoA reductase block IJ, can also be used as indicators of toxicity. This gastrointestinal disorder basket, the power to investigate by exterminating extinct ^! Noh. Gastrointestinal disorders, which are mentioned as side effects of clofibrate drugs, can also be used as indicators of toxicity. This gastrointestinal disorder can be examined by examining extinct matter. Ugly example)

The following examples illustrate the invention in more detail. In addition, the following examples (which are merely examples for specifically describing the present study and have no limiting meaning. Compound (R)-which is a ^ 3 agonist used in the present example) N- [3 -— [2- [2- (7-Hydroxy-9H-carbazolyl-2-yloxy) ethylamino] -11-hydroxyethyl] phenyl] methanesulfonamide. (R) — N— [5- [2- [2- (5,6,7,8-tetrahydro-1 9H-carbazolyl-2-isoleoxy) ethylamino] — 1-Hyd mouth xychetyl] —2-hydroxy [Feninole] methanesnolehonamide, diamide (R) -N- [5- [2- [2- (dibenzothiophene-3-isoleoxy) ethylamino] — 1-hydroxyxenotin] —2-hydroxyphene Ninore] methanesulfonamide, di-drug compound dW (R) -N- [5- [2- [2— (9 H—power E) Ethylamino] — 1-hydroxyethyl] — 2-hydroxyphenyl] methanesulfonamide, conjugated e (R) -N- [3- [2- [2-— (9 H—canolebazoyl) 2—yloxy) ethylamino] — 1-hydroxyethyl] phenyl] methanesulfonamide, iridile compound (R) _Ν '— [5—

[2- [2- (9-hydroxyl-2-yloxy) ethylamino] —1-hydroxyethyl] -1-hydroxyphenyl] —Ν, Ν-dimethylsulfamide, amide compound g (R ) — N '— [5- [2-— [2- (dibenzofuran-3-isoleoxy) ethylamino] — 1-hydroxyxethyl] —2-hydroxyphenyl] 1 N, N-dimethylsulfamide, h I (R) — N— [5— [2— [2— (9H—caffrebazol—2-yloxy) ethylamino] 1—1-hide mouth kisshethyl] 1-2—chlorophenyl] methanesulfonamide, Thing i I

(R) i N— [5- [2- [2- (9H—l-razole-1—yloxy) ethylamino] _ 1-Hydroxyethisole] -2-bromophenyl] methanesulfonamide.

[Compound a]

According to the method described in the above-mentioned production method, in (XIV), a compound of the formula (XV) in which R ³ ′ is a benzyloxy group and W is a double-fiber atom is reacted with dibromoethane represented by the formula (XV). And further reacted with benzylamine to give N-benzyl-2-

(7-Benzyloxy 9H-carbazolyl-2-yloxy) ethylamine This compound is reacted with a compound in which R ¹ ′ is a hydrogen atom in the HI formula (IV), and the nitro group is subsequently reduced. a By the usual method: ^ Salt.

R f = 0.8 (black form methanol = 4/1 (free form));

M a s s (m / e) 4 5 6 (MH +)

Further, the i-conjugation product b is disclosed in WO99 / 011431, and the i-conjugation products c to i are disclosed in Japanese Patent Application Laid-Open No. 9-246263.

Hydrochloride is used as a compound for examining chrysanthemum of the compounds a to i. These salts can be prepared by a conventional method.瞧 Example 1) Results of dysuria

Measurement of TO Force of Human Bladder Compression Muscle The measurement was performed according to the method of Takeda M. et al. (J. Pharm. Exp. Ther. 288, P1367-1373 (1999)). That is, to cause a fiber using the cuff Rebakoru ^{(0. 5 x 1 0- 6 M} ), it was tested compounds a, b, c, d, e, f, g, h, i, bow image乍用of propiverine. Compounds a, b, c, d, e, f, g, h, i, propiverine, oxyptinin, tolterodine 10 ⁷ , 10 ⁷ , ΙΟΛ 10 ⁸ , 10 10 ⁷ , 10 ⁷ , 10 10 -10 · ^5, 10Λ 10 "« force 10 ⁹ significantly relaxes the bladder pressure muscle in ^{^{M, 10- 9, 10 10,}} 10Λ 10 10- 9, 10 9, 10 10 10 10 9, ΙΟ- 9 in Μ It did not significantly relaxed. Iotaomikuron prop base phosphorus and each ΙΟ ^ Μ I spoon ^ ¾ a, ΙΟ compound b, 10. ¹⁰ M I匕合compound c, 10 ¹⁰ M compound d, lO I匕合compound e, 10 I When the compound was added to the bladder compressive muscle with a combination of f, lO compound g, 10¾1 compound h, and lO dani compound i, the compound was significantly relaxed as compared to «. ¾a, 10¾ compound b, 10 ¹⁰ M conjugated compound c, 10 ¹⁰ M compound d, ΙΟ. ⁸ ] ィ conjugated compound e, 10.¾ 匕 ridge f, Ιθ compound g, ΙΟ ^ ΙΟ 匕匕Compound h, lO— In was added the compound of the bladder pressure muscle was bow knitting than a job. Further 〖^ 10¾1 Tolterodine and each ΙΟ of Certainly a, lO compound b, 10 ¹⁰ M I匕合compound c, 10 ¹⁰ M I匕合Object d, 匕合 e e, 匕匕物 f f, 10¾1 compound g, 10 · ⁸匕匕 Compounds were added to the bladder compression muscle in combination with h, lO i-dang i, and it relaxed compared to the occupation.

Therefore, the remedy used in combination with the present invention showed a strong synergistic effect in treating incontinence and urinary incontinence, and was confirmed to be useful as a therapeutic agent for urinary incontinence.

According to Nagao et al.'S method (Journal 113, pl56-166 (1999)), the excitement of saliva secretion at lower doses was measured according to Nagao et al.'S method (Journal 113, pl56-166 (1999)). Inhibitory power was observed.

[Example 2] The screaming effect (I)

Mice induced obesity by feeding a high-fat diet for 2 months were given sibutramine (SIB; lmg kg), β3 agonist (compound; 0.3mg / kg, i-drug compound d; 0.3mg / kg, 3 mg / kg, compound g; 3 mg kg, 匕 conjugate h; lmg kg, 匕 conjugate i; lmg / kg), a certain compound is SIB and ^ 3f agonist (compound c, Compound d, compound ^ | ¾le, conjugated compound g, compound h, compound i) in combination (each dose is the same as above) were orally administered for 2 weeks, bred and weighed. SIB, 匕合化合物 Compound d, ィ合物 e, ィ合 g g, 匕合 h h, ィ合 i i i 職群に職体重にOn the other hand, 3 1 8

Significant weight loss was observed in the group administered the combination of SIB and compound g, SIB and compound h, SIB and compound i.

As a result, the Jinsatsu was recognized as having an excellent effect on Toba Man.

About the blood pressure increase as a side effect of sibutramine By using a drug and a pressure transducer, the blood pressure was reduced and the force was measured. Example 3) Manga effect (II)

Orlistat (l mg kg), 33 agonist (compound; 0.3 mg / kg, i-drug compound d; 0.3 mg / kg, i-did) compound e; 3mg / kg, i匕合compound g; 3 mg kg, i匕合compound h; lmg k _g, compound i; lmg / kg), or Orurisutatsuto and / 3 3f agonists (compound i匕合product The combined use of d, compound e, compound g, i-conjugation compound h, and compound I) (each dose was the same as above) was orally administered for 2 weeks, bred, and the body weight was measured. The oristat, compound 匕合 d, 匕合 e e, ィ合 g g, 匕合 h h, ィ合合 i i 戦に対し体重体重体重体重体重. Orlistat and compound c, orlistat and compound d, orlistat and compound e, orlistat and compound g, orlistat and compound h, orlisty Weight loss was observed in the stat and compound i co-administration groups.

Therefore, this project was recognized as having an excellent effect on Mandom.

Gastrointestinal disorders as side effects of orlistat (stomach stool, increased throat, abdominal pain, crane pressure) It is possible to investigate by clarifying the amount of medicine, wheat, «, ^: minutes. Ugly case 4) Urinary disease effect (I)

To mice, insulin (INS; 0.2 U / kg, intranasal administration), β 3 (compound a; 10 mg kg, 匕 ^ ^ ;; 0.3 mg / kg, 匕合合 d d; 0.3 mg / kg, 匕匕Compound e; 3 mg / kg, 匕 ^^ tig; 3 mg kg, 匕合 h h; lmgk _g , 匕合 i i; lmgkg each; «oral administration), or INS and ^ 3 p | Combination of Compound a, Compound 匕合 d, 匕合 e e, 匕合 g g, 匕合 h h, ィ合物 i) (each dosage and administration is the same as above) After administration, the fibers were woven 30 minutes later, and the amount of glucose contained in β was measured. As a result, a change in female value was observed upon administration of の, INS 合 a a, 合 c c, 匕合 d d, ィ合 e e, compound h, 合 i. There were no significant differences in the female values when INS and Compounds a and 11 ^ 3 and Compound I NS and Compound d, INS and Compound e, INS and Compound g, INS and Compound h, INS and Compound i were administered in combination. I was strong. Therefore, the project was shown to have an excellent uremic effect.

[Wei Example 5] The effect of withdrawal urine (II)

-Dalibenclamide (GL I; 10 mg / kg), β (compound a; lOmg / kg, 匕 ^ ^ c) c; 0.3 mg kg, 匕合物 d d; 0.3 mg kg, ィ合合3 mg / kg, 匕合 g g; 3 mg / kg, 匕 ^ ^ Ih; lmg kg, compound ^) i; lmg kg), or GLI and / 33ί agonist (compound a, lig compound c, ィOral administration of the combined use of the danigata compound d, the ehida compound e, the idaigad compound g, the idaida compound h, and the ihida compound i) (each dose is the same as described above) was immediately followed by glucose (lgkg). , Subcutaneous administration). One hour later, the fibers were woven, and the amount of glucose contained in the fiber was measured. GL I, compound a, compound d, d, y d, g, h, compound i There was almost no difference in the Tang value compared to the mice that underwent GLI and GLI and compound C, GLI and compound d, GLI and compound e, GLI and compound The combined administration of Compound g, GLI and Compound h, GLI and Compound i significantly reduced the sickle value. Therefore, the project was recognized as having an excellent uremic effect.

In this combination, no side effect of dalibenclamide {MU Tang was observed. [¾Example 6] ¾¾Urine disease effect (1 1 1)

Genetically diabetic mice were treated with rosiglitazone (ROS; 1 mg kg), β3 agonist (compound c; 0.3 mg / kg, compound d; 0.3 mg kg, 合 conjugated product e; 3 mg / kg, 匕 conjugated product g; 3Mgkg, i匕合compound h; lmgkg, compound i; lmgk _g), or R_〇_S and / 33 agonist (compound i匕合product d, i匕合compound e, compound g, i匕合compound h, i The combined use of the daggers i) (each dose was the same as above) was orally administered for 2 weeks. Thereafter, blood was collected, and the amount of glucose contained in β was measured. Insect administration of ROS, 匕合 c c, 匕合 d d, compound e, 匕合 g g, 匕合 h h, ィ合物Shaku 03 and compound Shaku 03 and compound 0, shaku 03 and compound 6, ROS and compound g, shaku03 and compound 1, ROS and compound i (the blood glucose level was significantly reduced).

力治件件にに «« «« 治;;.

In addition, the combined administration group showed a weight loss power compared to ROS warfare treatment, and there was no body weight gain which is a side effect of ROS. Case 7) Maleuria effect (IV)

Genetic diabetic mice were treated with acarbose (ACA; 1 mg / kg), β3 agonist (compound c; 0.3 mgkg, i-danigata d; 0.3 mgkg, i-danigata e; 3 mgkg, compound g; 3 mg / kg, compound h; lmg / kg, compound i; lmg / k _g), or ACA and ^ 3 agonist (compound compound d, i匕合compound e, compound g, i匕合compound h, i匕合Compound i) was administered orally for 2 weeks (each dose was the same as above). Then, the amount of glucose contained in β was measured. ACA, Compound 匕合 d, 匕合 e e, 匕合 g g, 匕合 h h, ィ合物 i showed no difference in male value, Males and Compounds 880 and Compounds, 808 and Compound 6, AC A and Compound I g, 880 and Compound 11, AC A and Compound i, decreased in male value in the combined administration group. .

Therefore, it was confirmed that the efficacy of this project was excellent in treating this disease. Ugly case 8] Antihyperlipidemic effect (I)

The use of pravastatin (PRA) in combination with a / 33 agonist enhances the antihyperlipidemic effect of vehicle dogs.]] According to Biochim. Biophys. Acta, 877, p50-60 (1986)), it has been shown that administration of PRA; 0.625-1.25 mgkg in vehicle dogs lowers blood cholesterol levels and blood triglyceride levels. You. In addition, it has been shown that bikino uses 33ί pharmacodynamics (livestock biochemistry 33, pl3-18 (1996)), so it can be converted to ^ la, b, c, d, e, f, g, h. , I are also expected to work. The combined use of pravastatin and a / 33 agonist with different mechanisms of action can be seen as a synergistic reduction in blood cholesterol levels and blood triglycerides.

However, the anti-hyperlipidemic effect was found to be excellent in this treatment.

[^ Example 9] Antihyperlipidemic effect (II)

Mice Bezafuiburato (BEZ; 3 mg / kg) , β 3 mm ( reduction ^ lc; 0.3mgk _g, I匕合product d; 0.3mgkg, of ^) e; 3mg / kg, I匕合product g; 3 mg lmgkg, compound # 3i; lmg / kg), or BEZ and / 33 agonists (compound compound d, iridani e, iridanig, g Combination of compound i) was administered orally for 2 weeks. Thereafter, blood was collected, and triglyceride contained in plasma was measured.靴ィ合物物物合 d d d 、、物物の物物物物物物物物物匕匕物物匕匕匕匕匕匕匕匕匕 d d d d d d d 雌compound 8 £ sigma and compounds, they wanted Toriguriserai cathodic at 8 £ and compound _6, BEZ and compounds g, 85 and compound 1, the combined administration group BEZ and compound i.

It is expected that the anti-hyperlipidemic effect which is excellent in this case will be achieved. All publications, patents, and patent applications cited in the present specification are hereby incorporated by reference in their entirety. According to the present invention, an anticholinergic agent, a monoamine reuptake inhibitor, a lipase inhibitor, an interstitial serotonin reuptake inhibitor, insulin, an insulin secretion agent, a biguanide, an α-dalcosidase inhibitor, insulin At least one selected from the group consisting of a sex improver, an HMG-Co Α reductase inhibitor, an anion conjugate, a clofibrate drug, and a nicotinic acid sickle IJ, and at least a compound having β 3 agonistic activity Therapeutic power provided. The therapeutic agent of the present invention has a therapeutic effect on micturition disorders, a Manila effect, a Tokara urinary disease effect, and a shelf-hememia effect.

Claims

The scope of the claims

1. Anticholinergic agent, monoamine reabsorption inhibitor, lipase inhibitor, isometric serotonin reabsorption inhibitor i-insulin, insulin sharing agent I, biguanide, α-darcosidase inhibitor ij, insulin-improving agent, HMG— A treatment comprising at least one selected from the group consisting of a CoA reductase inhibitor, an anion exchange resin, a clofibrate drug, and a nicotine suspension drug, and a compound having 33 agonistic activity. Dish

2./3 The compound having a labile activity is represented by the following formula (I), formula (II) or general formula (III). Or the salt thereof, or a salt thereof. ~ «Formula (I);

[In the formula, 1 ^ {represents a nitrogen atom, a halogen atom or an i-O-acid group, and R ² represents a {& -grade alkyl group or a benzyl group. R ³ (iOR, represents a halogen atom, a trifluoromethyl class alkyl group, a cascade group NR ⁴ R ⁴ ′, a nitro group or a cyano group, and an R 〖O atom, a lower alkyl group, a benzyl group or a substituted group R ⁴ and R ⁴ ′ may be the same or different, and may be different from each other; hydrogen atom, quaternary alkyl group, quaternary acyl group, benzyl group Or SO ₂ R ^5. R ⁵ represents a lower alkyl group or a benzyl group, represents a hydrogen atom, a diatomic (NH) or a sulfur atom, and the book represents an asymmetric carbon atom. Compound or its

HI 弒 (II);

Wherein indicates the R ⁶ (Contact atom or a methyl group, long ⁷ {per cent] atom, a halogen atom, 7j <group, Baie Njiruokishi Hiroshi amino group or hydroxymethyl group, R ⁸ {± _K containing Represents an atom, a hydroxymethyl group NHR ⁹ , SO ₂ NR ¹⁰ R ¹⁰ ′ or a nitro group, provided that R ⁹ represents an oxygen atom, a methyl group, SO ₂ R ″, a formyl group or a CONHR ¹² ′, and R ¹¹ is a lower alkyl group a benzyl group, or NR ¹⁰ R ¹⁰ 'showing a. Moreover, R ¹⁰ and R ^10' good hydrogen atoms be different same or mutually shows ί膽Arukiru or benzyl. R ¹² Contact R represents a nitrogen atom or a quaternary alkyl group, R ¹² represents a hydrogen atom or a quaternary alkyl group, η is 1 or 2, and represents a W doublet atom, an oxygen atom or a sulfur atom. when η is 1, at one of R ¹³ or R ¹⁴ is a hydrogen atom, the other (Atom, when the Amino group Asechiruamino group also (showing a contact group. Eta force 2, 1¾ ¹⁴ {in per cent _) atom, 1 ¹³ {per cent] <atom, an amino group Asechiruami amino group also 〖Contact纖a group. * 1 (indicates asymmetric carbon atom, * 2 and * 3 are in the R ¹² and old R ¹ ⁴ is not each a hydrogen atom means an asymmetric carbon atom.] with a compound or its the indicated

"^ Wipe (III);

[In the formula, R ^{6 represents a} fc element atom or a methyl group; R ⁷ represents an oxygen atom, a halogen atom, a hydroxyl group, a benzyloxy amino group or a hydroxymethyl group, and a shaku ⁸ (a hydrogen atom or a hydroxymethyl group. A tyl group, NHR ⁹ , SO ₂ NR ¹⁰ R ¹⁰ ′ or a group, provided that R ⁹ represents an iodine atom, a methyl group SO ₂ R ″, a formyl group or a CONHR ¹² ′, and R ¹¹ represents a ί & class alkyl Hiroshi benzyl or NR ¹ oR ¹⁰ 'showing a. Moreover, R ¹⁰ and R ^10' is good be different same or mutuallyヽhydrogen atom, an ig及alkyl group or a benzyl group. R ¹² '(fc-containing Represents an iSI or alkyl group; R ¹² represents an oxygen atom or a lower alkyl group; WI represents a nitrogen atom, an additional atom, a sulfur atom, or a methylene group; atom, with R ¹⁷ (Contact atom of oxygen or sulfur atom, have some R ¹⁵ In either one mosquito冰素atoms R ^16, the other side ί per cent atom, an amino group, Asechiruamino a group also (our group. Further, W is in which hydrogen atoms both R ¹⁵ and R ¹⁶ methylene groups , R ¹⁷ (atom atom, amino group, acetyla It represents a mino group or an acid group. * Hi, indicates an asymmetric carbon atom, the age is * 2 R ^{1 2} month赚alkyl group就an asymmetric carbon atom. ] Or a salt thereof

3. The treatment according to claim 1 or 2, wherein the treatment is pollakiuria or urine, which comprises at least an anticholinergic agent and a compound having 3p | potency activity.

4. The treatment according to claim 3, wherein the treatment is selected from the group consisting of anticholinergic drugs, flavoxet hydrochloride, oxyptinin hydrochloride, propiverine hydrochloride, and tolterodine.

5. The dish according to claim 3, wherein if ^ indicates that the anticholinergic agent is any of oxyptinin hydrochloride, propiverine and tolterodine.

6. A fertilizer comprising at least one selected from the group consisting of monoamine reuptake inhibitors, lipase inhibitors, and 31-meter serotonin reuptake inhibitors, and a compound having β3p を activity. The treatment according to claim 1 or 2, wherein the treatment is

7. The dish according to claim 6, comprising at least a compound having monoamine re-absorption inhibition and ^ 3 agonistic activity.

8. The dish according to claim 6 or 7, wherein the monoamine reuptake inhibitor is any one of sibutramine, milnacipran, duloxetine, and benlafaxine.

9. The fiber as claimed in claim 6, wherein the monoamine reabsorption inhibitor is sibutramine.

10. The treatment according to claim 6, comprising at least a lipase inhibitor and a compound having β3 agonist activity ft;

1 1. The lipase inhibitor is orilstat! Jin described in either claim 6 or 10 as ^

1 7. The dish according to claim 6, wherein the dish contains at least a general serotonin willing and blocking IJ and a compound having β3¾r activity.

13. The method according to claim 6, wherein f-scale serotonin ニン n and inhibition 阻 j are fusoleoxetine, senoletraline, paroxetine, and fluvoxamine.

1 4. Including at least one selected from the group consisting of insulin, insulin secretion-promoting agent, biguanide, c-dalcosidase inhibitor, and insulinotropic agent, and a compound having β3 agonistic activity The treatment according to claim 1 or 2, wherein the treatment is type II diabetes mellitus.

15. The dish according to claim 14, comprising at least insulin and a compound having β3 agonist activity.

1 6. The dish according to claim 14, wherein the dish contains at least insulin insulin © 1 ^ and a compound having a / 33 synergistic activity.

17. The method according to claim 14, wherein the insulin secreting agent is glibenclamide, glibizide, gliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, chlorpropamide, glicloviramide, meglitinide, levaglinide, nateglinide, mitiglinide. Also, (the cure described in 16).

18. The treatment according to claim 14 or 16, wherein the insulin secretion JS ^ fiJ is dalibenclamide.

1 9. The dish according to claim 14 or 16, wherein insulin secretion ^ i ^ J power levaglinide, nateglinide, mitiglinide is!} # Ί¾.

20. The dish according to claim 14, comprising at least a biguanide and a compound having / 33 p |

21. The treatment according to claim 14 or 20, wherein the biguanide is metformin, bufolmin! TO.

22. The treatment according to claim 1, wherein the treatment includes at least an α-dalcosidase inhibitor and a compound having β3 agonist activity.

23. The treatment according to claim 14 or 22, wherein the treatment is α-dalcosidase inhibitor ', acarbose, voglibose, miglitol, or emiglitate.

24. The jito according to claim 14 or 22, wherein the a-dalcosidase inhibitor is acarbose.

25. Insulin »It should contain at least a 改善 'Ι4 improver and a compound having / 33 agonistic activity! The cure according to claim 14, wherein

26. The dish according to claim 14 or 25, wherein the insulin fiber property improving agent is troglitazone, pioglitazone, rosiglitazone, MCC-555, GI-262570, JTT-501, and KRP-297.

27. The treatment according to claim 14 or 25, wherein the insulin sensitizer is rosiglitazone.

28. The treatment according to claim 14 or 25, wherein the properties of the insulin 赚 ameliorating agent are MCC-555, GI-262570, JTT-501, and KRP-297.

29. HMG— selected from the group consisting of Co A reductase inhibitors, anion conjugates, clofibrate drugs, and nicotinic acid drugs, and compounds with β3 agonist activity 3. The therapeutic agent according to claim 1, which is a therapeutic agent for hyperlipidemia, which comprises at least

30. The treatment according to claim 29, comprising at least an HMG-CoA reduction inhibitory IJ and a compound having β3 agonist activity.

31. The treatment according to claim 29 or 30, wherein it is observed that HMG-CoA reductase inhibitor is pravastatin, simpastatin, flupastatin, atorvastatin, cerivastatin, nisvastatin, or S-4522.

3 2. HMG-co

Claims to be pravastatin

29 Dish described in 9 or 30

33. The method according to claim 29 or 30, wherein HMG-CoA reduction is an inhibitor of simvastatin, fluvastatin, vastatin at mouth, cerivastatin, nispastatin, and S-4522. Treatment

31. The treatment according to claim 29, wherein the composition contains at least anion exchange ^^ fat and a compound having / 3 3 p | force activity.

3 5. The dish according to claim 29, wherein the anion is cholestyramine or colestimide.

30. The treatment according to claim 29, comprising at least a clofibrate drug and a compound having β3 agonist activity; m

3 7. The method according to claim 29, wherein the clofibrate drug ij is clofibrate, simfibrate, clinofibrate, bezafibrate, fenofibrate, ciprofibrate, or gemfibrozil. Cure

3 8. The treatment according to claim 29 or claim 36, wherein the drug is clofibrate-based drug bezafibrate.

30. The treatment according to claim 29, comprising at least a nicotinic acid-based drug and a compound having an activity of 33 gf.

40. The treatment according to claim 29 or 39, wherein the nicotinic acid-based drug is nicotinic acid, dicomole, niceritol, or tocopherol nicotinate.

4 1. Anticholinergic agents, monoamine reuptake inhibitors, revase inhibitors, selective serotonin reuptake inhibitors, insulin, insulin secretagogues, biguanides, α-dalcosidase inhibitors, insulin improvers, HMG— Selected from the group consisting of CoA reductase inhibitor, anion exchange resin, clofibrate, and nicotinic acid (i.e., i33 f¾) activity A treatment method comprising administering a treatment containing at least a compound having

42. The compound having β 3 -producing Kr activity is a compound represented by the following formula (I) or “^ formula (II) or formula (III), or a salt thereof. Treatment according to item 41 m

Wipe (I);

[Wherein, 1 1 (ぉ) represents an atom, a halogen atom, or an i-acid group, and R ² represents a lower alkyl group or a benzyl group.] R ³ fiOR, a halogen atom, trifrenoreolomethyl-lower-alkyl A lower acyl group NR ⁴ R ⁴ ′, a nitro group or a cyano group; RfeK, a lower alkyl group, a benzyl group or a lower acryl group which may have a male group; R ⁴ and R ⁴ ′ Represents a hydrogen atom, a lower alkyl group, an iSacyl group, a benzyl group or SO ₂ R ⁵ which may be the same or different from each other, and R ⁵ represents a {quaternary alkyl group or a benzyl group; ^^ represents an atom (NH) or a sulfur atom, * represents an asymmetric carbon atom.

Wiping (II);

(M)

[In the formula, R ⁶ ifc represents an elemental atom or a methyl group, R ⁷ i represents an elemental atom, a halogen atom, a hydroxyl group, benzyloxy represents an amino group or a hydroxymethyl group, and R ⁸ i represents an elemental atom or hydroxymethyl. Represents a group, NHR ⁹ , SO ₂ NR ¹⁰ R ¹⁰ ′ or a nitro group. However, R ⁹ {i * atom, a methyl group S0 ₂ R ", indicates a formyl group or C0NHR ¹² ', R ¹¹ is {& loweralkyl Hiroshi benzyl Represents a group or NR ¹⁰ R ¹⁰ ′. R ¹⁰ and R ¹⁰ ′ each represent a hydrogen atom, which may be the same or different from each other, and a ί & class alkyl group or a benzyl group. R ¹² 'ifc is a lower alkyl group. In addition, R ¹² represents an oxygen atom or a lower alkyl group. Η is 1 or 2, and W (i represents an i atom, an oxygen atom or a sulfur atom. When n is 1, R ^{13 represents} in either one hydrogen atom of R ^14, the other (Contact J atom, when amino grave Asechiruamino group also (our group showing a. n is 2, at 1¾ ¹⁴ (per cent] <atom, ³ ( per cent] atom, an amino group, Asechiruami Roh represents a group also. * 1 (asymmetric carbon atoms exhibiting a ί Contact J groups, * 2 and * 3 feet ¹² Oyobi! ^ ^'4 are not each a hydrogen atom Represents an asymmetric carbon atom.] Or a compound thereof

"^ Formula (III);

[In the formula, R ⁶ represents an oxygen atom or a methyl group, R ⁷ represents an oxygen atom, a halogen atom, a hydroxyl group, a benzyloxy group, an amino group or a hydroxymethyl group, and R ⁸ represents an oxygen atom or a hydroxymethyl group. Tyl group NHR ⁹ , SO ₂ NR ¹⁰ R ¹⁰ ′ or nitro group, provided that R ⁹ (O atom, methyl ¾SO ₂ RH, formyl group or CONHR ¹² ′, R】 ¹ is lower alkyl group, benzyl or NR ¹ oR ¹⁰ 'showing a. Moreover, R ¹⁰ and R ^10' good hydrogen atoms be different same or another, indicating the grade alkyl group or a benzyl group. R ¹² 'ί Contact J atom or Represents a primary alkyl group, R ¹² represents a fc element atom or a {secondary alkyl group, W represents a secondary nitrogen atom, an oxygen atom, a sulfur atom, or a methylene group, and W represents a carbon atom, an oxygen atom, or a sulfur atom. in the age R ¹⁷ (your atom, a R ¹⁵ Any in either one force ¾ atom of R ^16, the other side 〖Contact J <atom, an amino group, Asechiruamino a group also {per cent acid. Further, age R ¹⁵ and R ¹⁶ of W force styrene group in even hydrogen atom, R ¹⁷ 〖Contact atom, an amino group, Asechirua amino represents a group also (Contact J groups. * 1 indicates an asymmetric carbon atom, in a * 2 R ¹² forces loweralkyl group asymmetric Fibers of carbon atoms.] Compound or its;

43. The treatment according to any one of claims 41 or 42, wherein the method is a method for treating step resuscitation or urinary incontinence, comprising administering a therapeutic agent containing at least an anticholinergic agent and a compound having β3 agonist activity. Treatment

4 4. Selected from the group consisting of monoamine reuptake inhibitors, lipase inhibitors, and large-scale serotonin reuptake inhibitors. The method according to any one of claims 41 to 42, wherein the method is a method for treating obesity.

4 5.Selected from the group consisting of insulin, insulin secretion inhibitors, biguanides, α-dalcosidase inhibitors, and insulinotropic agents (at least one of the compounds with β3 agonistic activity A method for treating diabetes according to any one of claims 41 and 42, wherein the treatment is a method for treating diabetes, which comprises administering a treatment for diabetes.

4 6. Select from the group consisting of HMG_CoA reductase inhibitor, anion exchange lipid, clofibrate drug, and nicotinic acid drug. A method for treating hyperlipidemia, wherein TO is a method for treating hyperlipidemia, comprising administering a treatment comprising at least: